Combine and conquer: challenges for targeted therapy combinations in early phase trials
Open accessAbstract
Our increasing understanding of cancer biology has led to the development of molecularly targeted anticancer drugs. The full potential of these agents has not, however, been realised, owing to the presence of de novo (intrinsic) resistance, often resulting from compensatory signalling pathways, or the development of acquired resistance in cancer cells via clonal evolution under the selective pressures of treatment. Combinations of targeted treatments can circumvent some mechanisms of resistance to yield a clinical benefit. We explore the challenges in identifying the best drug combinations and the best combination strategies, as well as the complexities of delivering these treatments to patients. Recognizing treatment-induced toxicity and the inability to use continuous pharmacodynamically effective doses of many targeted treatments necessitates creative intermittent scheduling. Serial tumour profiling and the use of parallel co-clinical trials can contribute to understanding mechanisms of resistance, and will guide the development of adaptive clinical trial designs that can accommodate hypothesis testing, in order to realize the full potential of combination therapies.
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Combination therapies using two or more therapeutic agents can be superior to single-agent therapies in the treatment of cancers.
“Combination therapies using two or more therapeutic agents can be superior to single-agent therapies in the treatment of cancers (1–3).”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [2]
Due to redundancy of signals that control tumor growth, drug combinations targeting multiple key nodes in growth-promoting signaling pathways have led to increasing FDA approvals.
“Due to the redundancy of signals that control tumor growth, drug combinations targeting multiple key nodes in growth-promoting signaling pathways has led to increasing Food and Drug Administration (FDA) approvals.75,76”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [75]
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“…for each individual drug compared to when they are administered alone; (3) minimising the development of drug resistance or relapse; (4) achieving high cancer selectivity (cancer cell killing without affecting normal cells); and (5) expanding the range of treatment-responsive cancers [18, 19].”
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- Authors
- Lopez, J. S., & Banerji, U.
- Affiliations
- Royal Marsden NHS Foundation Trust (GB)
- Corresponding author
- Lopez, Juanita S.
- Banerji, Udai
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2016-07-05
- Volume
- 14
- Issue
- 1
- Pages
- 57-66
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- PMC
- PMC6135233
- OpenAlex
- W2471562228
- Cited by
- 394
- References
- 120
- Citations by year
- 2026: 36 · 2025: 60 · 2024: 60 · 2023: 48 · 2022: 27 · 2021: 38 · 2020: 31 · 2019: 29 · 2018: 37 · 2017: 24 · 2016: 3 · 2015: 1
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Reviews Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (11566, 21195, 22897)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- combination targeted therapy, acquired drug resistance, de novo resistance, clonal evolution, intermittent dosing, adaptive trial design, co-clinical trials
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Clinical Trials as Topic, Combined Modality Therapy, Humans, Immune System, Neoplasms, Patient Selection, Drug Resistance, Neoplasm, Cell Line, Tumor, Systems Biology, Molecular Targeted Therapy, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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